Next Article in Journal
Toward of Safer Phenylbutazone Derivatives by Exploration of Toxicity Mechanism
Previous Article in Journal
Chiroptical Symmetry Analysis: Exciton Chirality-Based Formulae to Understand the Chiroptical Responses of Cn and Dn Symmetric Systems
Open AccessArticle

Identification of Novel Potential Inhibitors of Pteridine Reductase 1 in Trypanosoma brucei via Computational Structure-Based Approaches and in Vitro Inhibition Assays

1
Research Unit in Bioinformatics (RUBi), Department of Biochemistry and Microbiology, Rhodes University, P.O. Box 94, Grahamstown 6140, South Africa
2
College of Veterinary Medicine, Animal Resources and Biosecurity (COVAB), Makerere University, P.O. Box 7062, Kampala 00256, Uganda
3
Department of Biochemistry and Microbiology, Rhodes University, Grahamstown 6140, South Africa
4
Centre for Chemico- and Biomedicinal Research, Rhodes University, Grahamstown 6140, South Africa
*
Author to whom correspondence should be addressed.
Member of the Trypanogen Consortium, www.trypanogen.net.
Academic Editor: Tiziano Tuccinardi
Molecules 2019, 24(1), 142; https://doi.org/10.3390/molecules24010142
Received: 12 November 2018 / Revised: 20 December 2018 / Accepted: 24 December 2018 / Published: 1 January 2019
Pteridine reductase 1 (PTR1) is a trypanosomatid multifunctional enzyme that provides a mechanism for escape of dihydrofolate reductase (DHFR) inhibition. This is because PTR1 can reduce pterins and folates. Trypanosomes require folates and pterins for survival and are unable to synthesize them de novo. Currently there are no anti-folate based Human African Trypanosomiasis (HAT) chemotherapeutics in use. Thus, successful dual inhibition of Trypanosoma brucei dihydrofolate reductase (TbDHFR) and Trypanosoma brucei pteridine reductase 1 (TbPTR1) has implications in the exploitation of anti-folates. We carried out molecular docking of a ligand library of 5742 compounds against TbPTR1 and identified 18 compounds showing promising binding modes. The protein-ligand complexes were subjected to molecular dynamics to characterize their molecular interactions and energetics, followed by in vitro testing. In this study, we identified five compounds which showed low micromolar Trypanosome growth inhibition in in vitro experiments that might be acting by inhibition of TbPTR1. Compounds RUBi004, RUBi007, RUBi014, and RUBi018 displayed moderate to strong antagonism (mutual reduction in potency) when used in combination with the known TbDHFR inhibitor, WR99210. This gave an indication that the compounds might inhibit both TbPTR1 and TbDHFR. RUBi016 showed an additive effect in the isobologram assay. Overall, our results provide a basis for scaffold optimization for further studies in the development of HAT anti-folates. View Full-Text
Keywords: Human African Trypanosomiasis; pteridine reductase 1; PTR1; DHFR; anti-folates; anti-trypanosomal agents; molecular dynamics; dynamic residue network analysis; binding free energy; isobologram assay Human African Trypanosomiasis; pteridine reductase 1; PTR1; DHFR; anti-folates; anti-trypanosomal agents; molecular dynamics; dynamic residue network analysis; binding free energy; isobologram assay
Show Figures

Graphical abstract

MDPI and ACS Style

Kimuda, M.P.; Laming, D.; Hoppe, H.C.; Tastan Bishop, Ö. Identification of Novel Potential Inhibitors of Pteridine Reductase 1 in Trypanosoma brucei via Computational Structure-Based Approaches and in Vitro Inhibition Assays. Molecules 2019, 24, 142.

Show more citation formats Show less citations formats
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Back to TopTop